Philip Urban, Alexandre Abizaid, Ian T. Meredith, Stuart J. Pocock, Didier Carrié, Christoph Naber, John Gregson, Samantha Greene, Hans Peter Stoll and Marie-Claude Morice for the LEADERS FREE Investigators Biolimus-Coated vs. Bare-Metal Coronary Stents in High Bleeding Risk Patients

Disclosure Statement of Financial Interest Affiliation / Financial Relationship Grant / Research Support Consulting Fees / Honoraria Company Biosensors Europe Edwards Lifesciences Terumo Abbott Vascular Within the past 12 months, I, Philip Urban, have had a financial interest / arrangement or affiliation with the organization(s) listed below.

High Bleeding Risk Patients (HBR) Mostly excluded from device and APT trials Never specifically studied Current guideline recommendations: BMS + one month DAPT DES + “shortened” DAPT

BioFreedom™ Drug Coated Stent (DCS) Selectively Micro-Structured Surface Holds Drug in Abluminal Surface Structures Potential Advantages: Avoid any possible polymer-related adverse effects Rapid drug transfer to vessel wall (98% within one month 2 ) Safe to shorten DAPT? BA9 TM Drug 10 Times More Lipophilic than Sirolimus 1 SirolimusZotarolimusEverolimusBiolimus A9 TM % +/- 2.8% (valid for all drugs test) 1. Data on file at Biosensors Intl; 2. Tada et al., Circ Cardiovasc Interv 2010;3;

Median In-Stent LLL at 12-month Follow-up 2 nd Cohort – Primary Endpoint N = 31 N = 35 p = (non-inferiority) Costa R et al. JACC interv (published online October 11, 2015 – DOI /j.jcin )

For patients with a high bleeding risk, using one month DAPT, can the BioFreedom DCS be shown to be as safe and more effective than a Gazelle BMS? Hypothesis

LEADERS FREE Trial Design Prospective, double-blind randomized (1:1) trial 2466 High bleeding risk (HBR) PCI patients vs. DAPT mandated for 1 month only, followed by long-term SAPT BioFreedom™ DCS Gazelle™ BMS Primary safety endpoint: Composite of cardiac death, MI, definite / probable stent thrombosis at 1 year (non-inferiority then superiority) Primary efficacy endpoint: Clinically-driven TLR at 1 year (superiority)

Inclusion Criteria (One or More) Age ≥ 75 years OAC planned after PCI Baseline Hb < 11g / dl or transfusion during prior 4 weeks Planned major surgery (within next year) Cancer diagnosed or treated ≤ 3 years Creatinine clearance < 40 ml / min Hospital admission for bleeding during past year Thrombocytopenia (< / mm3) Any prior intra-cerebral bleed Any stroke during the past year Severe liver disease NSAID or steroids planned after PCI Anticipated poor DAPT compliance for other medical reason

Trial Organization

Determination of Trial Size Predicted event rates in BMS control arm Composite safety endpoint (cardiac death, MI and ST) 8% Efficacy endpoint (clinically-driven TLR) 10% Patients per group: 1228 Both with one-sided alpha Endpoints Safety: > 80% power to demonstrate non-inferiority with margin 3.2% Efficacy: > 80% power to detect a 3.3% reduction in c-TLR

Enrollment and Follow-Up 2466 patients randomized 16 with no PCI performed 18 with no PCI performed 22 (1.8%) patients withdrew before 12-month visit or Were lost to FU 25 (2.0%) patients withdrew before 12-month visit or were lost to FU 1189 (98.2%) completed 12-month visit or died 1196 (98.0%) completed 12-month visit or died 1,227 BMS1,239 DCS 1,211 analyzed (modified ITT) 1,221 analyzed (modified ITT)

Inclusion Criteria Applied (1.7 criteria / patient)

Baseline Characteristics None of the baseline characteristics differ at p < 0.05

Index Procedure None of the procedure characteristics differ at p < 0.05

Index Procedure (Continued) None of the procedure characteristics differ at p < 0.05

Antithrombotic Medication at Discharge % None of the regimens differ at p < 0.05 * Any oral anticoagulant + DAPT

Primary Efficacy Endpoint (Clinically-Driven TLR) Cumulative Percentage with Event Days 0 9.8% 5.1% p for superiority < Number at Risk DCS BMS days chosen for assessing primary EP to capture potential evens driven by the 360 day FU contact %

Primary Efficacy Endpoint Difference: -4.8% (95% CI = -6.9% to -2.6%) HR 0.50, (95% CI = 0.37 – 0.69) p<0.001 for superiority

Secondary Efficacy Endpoints % p = 0.004p < p < 0.005

Primary Safety Endpoint (Cardiac Death, MI, ST) Cumulative Percentage with Event Days0 12.9% 9.4% Number at Risk DCS BMS p = for superiority days chosen for assessing primary EP to capture potential events driven by the 360 day FU contact %

Primary Safety Endpoint Risk difference: -3.6% (95% CI -6.1% to -1.0%) HR 0.71, (95% CI = 0.56 – 0.91) p < for non-inferiority p = for superiority * 3rd Universal definition of MI, Thygesen K et al Circulation 2012;126:2020 –2035 ARC definition, Cutlip D et al. Circulation 2007; 115:

Components of Safety Endpoint % p = 0.01 p = 0.70 p = 0.19

Selected Secondary Safety Endpoints % None of these endpoints differ at p < 0.05

Subgroups Composite safety endpoint (cardiac death, MI, ST) Hazard Ratio (95% CI)

Efficacy endpoint (clinically driven TLR) Subgroups (continued) Hazard Ratio (95% CI)

DAPT During Follow-Up Day Since Randomization SAPT DAPT 94.9% 9.5% DAPT= dual antiplatelet treatment or clopidogrel alone + vitamin K antagonist during first 30 days %

Bleeding During 12 Months Follow-Up % p = 0.55p = 0.68p = 0.96

Conclusions LEADERS FREE is the first randomized clinical trial dedicated to HBR patients Such patients are often excluded from stent and drug trials, constitute a rapidly growing proportion of PCI candidates and suffer high event rates Together with a one-month only DAPT course, the use of a BA9-DCS was both significantly safer and more effective than a control BMS in HBR patients

LEADERS FREE published online October 14, 2015

Leaders Free